The loss of acquired language and motor skills are two main diagnostic criteria for Rett Syndrome (RTT), a devastating developmental disorder caused by known mutations in the MECP2 gene. RTT is characterized by apparently normal development until 6 to 18 months of age followed by a ruinous regression phase that robs RTT children of their ability to speak, as well as leading to major motor dysfunction, breathing irregularities, digestive problems, gait abnormalities and other symptoms. While the genetic basis of the syndrome is understood, much less is known about the cortical alterations associated with it and what skills and abilities may yet be preserved. From clinical observations, we and others contend that these mostly non-verbal children have much greater abilities to understand speech than might at first be apparent. But anecdotal evidence and behavioral assays are inadequate for assessing potentially preserved speech-language function and there is a clear need to bring modern neurophysiological techniques to bear on this issue. In this project, high-density electrophysiological recordings allied with novel systems-identification data-analytic approaches will allow for a direct assessment of the extent of preserved speech reception abilities in RTT. The overarching goal of this project is to develop a thorough neurophysiological quantification of receptive auditory speech capabilities in RTT to deepen our understanding of this disorder. The proposed methods are likely the only feasible way to obtain functional brain measures in RTT, since magnetic resonance imaging has only been obtained under sedation in these children. The project takes a systematic approach to assaying speech-reception, moving from measures of basic phonemic processing, to measures of semantic processing, and in turn to measures that assay the processing of the highly dynamic speech envelope itself during natural speaking conditions. In this way, we can assess the fundamental building blocks of speech processing. The second major clinical symptom of RTT, loss of motor abilities affecting hands, arms, and legs, will also be examined using a novel electrophysiological approach. The processing of semantic auditory information involving action words that involve body parts (e.g. leg and kick) elicits activity in the corresponding parts o motor cortex. If motor impairments in RTT are primarily due to motor cortex dysfunction, then semantic processing for action words should be impaired relative to non-action words. As such, this paradigm represents a potentially powerful functional examination of motor cortical function in RTT. Taken together, the proposed project will examine two fundamental aspects of RTT in a quantitative way using a combination of well-established and cutting-edge methodologies. The derived knowledge could greatly impact ongoing development of assistive technologies to support more effective communication by these individuals with their caregivers and environment. In addition, a thorough quantitative description of two main symptoms of the disorder should lead to an enhancement in determining phenotype-genotype relations as well as an outcome measure for pharmacological clinical trials. PUBLIC HEALTH RELEVANCE: Rett Syndrome, a devastating neuro-developmental disorder that affects about 1 in 10,000 females, is characterized by a regressive loss of acquired spoken language and motor capabilities during the first two years of life. In patients who do not produce speech and lack motor abilities to respond to spoken words in a controlled manner, it is all too common to assume a more general lack of speech capabilities, but recent evidence suggests that this is likely not a valid assumption. There are now several reports indicating altogether greater receptive language processing skills in RETT children. This project therefore aims at developing widely applicable quantitative tests of the most important aspects of receptive speech processing using objective neurophysiological methods allied with novel systems identification data-analytic approaches. The goal is to determine just how intact the receptive speech system is in RETT, with important implications for the development of assistive communication devices for these oft-neglected children.